Diseases of the central nervous system remain among the most compelling maladies known to humankind. This is because neurological disorders are typically devastating to affected patients and their families, often robbing individuals of the qualities that we most strongly associate with being human, and because the vast majority of neurological and neurodegenerative disorders lack effective therapies. In the 1980s and 1990s, the advent of molecular genetics approaches to map and identify disease genes laid the foundation for a prodigious advance in our understanding of the pathogenic basis of numerous important neurological disorders.
Valproic acid (VPA) is widely used as an anticonvulsant, but therapy with the drug has been associated with hepatotoxicity, either reversible hepatic dysfunction or irreversible hepatic failure. Both clinical and experimental studies have revealed several VPA-related biochemical abnormalities in the liver: inhibition of the oxidation and synthesis of fatty acids and inhibition of gluconeogenesis, urea synthesis, oxidative phosphorylation, and the glycine cleavage system. Other abnormalities noted include alteration in the protein conformation of the internal mitochondnal membrane, hyperammonemia, and increased bile flow. The mechanisms of such hepatotoxicity, whether mediated by VPA or by its metabolites, are still little understood. Susceptibility to VPA hepatotoxicity may be enhanced by such conditions as starvation, inborn errors of metabolism, additional neurological disease, and concomitant administration of enzyme-inducing drugs.
The potential involvement of free radical or oxidative damage in the pathogenesis of human disease has received an enormous amount of study in the last decade. Free radicals are atoms or molecules with unpaired electrons in their outer orbits, making them highly reactive with macromolecular structures, leading to cellular injury and homeostatic disruption. Free radicals are produced as a byproduct of normal metabolism, and endogenous mechanisms exist to reduce their formation or enhance their inactivation. Disruption of the prooxidant and antioxidant balance in favor of the former may be a potential fundamental mechanism of human disease. A large body of evidence supports the concept that increased production of free radicals causes or accentuates neuronal injury and leads to disease, and this evidence has recently been reviewed. Therapy aimed at boosting antioxidant defenses or reducing pro-oxidant production with free radical scavengers or antioxidants may be efficacious in preventing, ameliorating, or arresting many neurologic diseases.
Managing acute pathology of often relies on the addressing underlying pathology and symptoms of the disease. There is currently a need in the art for new compositions to treatment or delay of the onset of neurological disorders and its associated complications progression.